{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:13:28Z","timestamp":1790802808358,"version":"4.1.0"},"reference-count":77,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2022,4,5]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">The onset and mechanisms of endothelial\u2010to\u2010mesenchymal transition (EndMT) in mitral valve (MV) leaflets following myocardial infarction (MI) are unknown, yet these events are closely linked to stiffening of leaflets and development of ischemic mitral regurgitation. We investigated whether circulating molecules present in plasma within days after MI incite EndMT in MV leaflets.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">We examined the onset of EndMT in MV leaflets from 9 sheep with inferior MI, 8 with sham surgery, and 6 na\u00efve controls. Ovine MVs 8 to 10\u00a0days after inferior MI displayed EndMT, shown by increased vascular endothelial cadherin\/\u03b1\u2010smooth muscle actin\u2013positive cells. The effect of plasma on EndMT in MV endothelial cells (VECs) was assessed by quantitative polymerase chain reaction, migration assays, and immunofluorescence. In vitro, post\u2010MI plasma induced EndMT marker expression and enhanced migration of mitral VECs; sham plasma did not. Analysis of sham versus post\u2010MI plasma revealed a significant drop in the Wnt signaling antagonist sFRP3 (secreted frizzled\u2010related protein 3) in post\u2010MI plasma. Addition of recombinant sFRP3 to post\u2010MI plasma reversed its EndMT\u2010inducing effect on mitral VECs. RNA\u2010sequencing analysis of mitral VECs exposed to post\u2010MI plasma showed upregulated FOXM1 (forkhead box M1). Blocking FOXM1 reduced EndMT transcripts in mitral VECs treated with post\u2010MI plasma. Finally, FOXM1 induced by post\u2010MI plasma was downregulated by sFRP3.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">Reduced sFRP3 in post\u2010MI plasma facilitates EndMT in mitral VECs by increasing the transcription factor FOXM1. Restoring sFRP3 levels or inhibiting FOXM1 soon after MI may provide a novel strategy to modulate EndMT in the MV to prevent ischemic mitral regurgitation and heart failure.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.121.023695","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T09:18:10Z","timestamp":1648545490000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Wnt Site Signaling Inhibitor Secreted Frizzled\u2010Related Protein 3 Protects Mitral Valve Endothelium From Myocardial Infarction\u2013Induced Endothelial\u2010to\u2010Mesenchymal Transition"],"prefix":"10.1161","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0097-4713","authenticated-orcid":false,"given":"Zahra","family":"Alvandi","sequence":"first","affiliation":[{"name":"Vascular Biology Program Boston Children\u2019s Hospital Boston MA"},{"name":"Department of Surgery Harvard Medical School Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5481-7524","authenticated-orcid":false,"given":"Yasufumi","family":"Nagata","sequence":"additional","affiliation":[{"name":"Cardiac Ultrasound Laboratory Massachusetts General HospitalHarvard Medical School Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia Silva Ara\u00faujo","family":"Passos","sequence":"additional","affiliation":[{"name":"Center for Excellence in Vascular Biology Brigham and Women\u2019s Hospital Harvard Medical School Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9625-6259","authenticated-orcid":false,"given":"Ali","family":"Hashemi Gheinani","sequence":"additional","affiliation":[{"name":"Department of Surgery Harvard Medical School Boston MA"},{"name":"Broad Institute of MIT and Harvard Cambridge MA"},{"name":"Department of Urology Boston Children\u2019s Hospital Boston MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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